de Wet Heidi, Proks Peter, Lafond Mathilde, Aittoniemi Jussi, Sansom Mark S P, Flanagan Sarah E, Pearson Ewan R, Hattersley Andrew T, Ashcroft Frances M
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
EMBO Rep. 2008 Jul;9(7):648-54. doi: 10.1038/embor.2008.71. Epub 2008 May 23.
Activating mutations in the pore-forming Kir6.2 (KCNJ11) and regulatory sulphonylurea receptor SUR1 (ABCC8) subunits of the K(ATP) channel are a common cause of transient neonatal diabetes mellitus (TNDM). We identified a new TNDM mutation (R826W) in the first nucleotide-binding domain (NBD1) of SUR1. The mutation was found in a region that heterodimerizes with NBD2 to form catalytic site 2. Functional analysis showed that this mutation decreases MgATP hydrolysis by purified maltose-binding protein MBP-NBD1 fusion proteins. Inhibition of ATP hydrolysis by MgADP or BeF was not changed. The results indicate that the ATPase cycle lingers in the post-hydrolytic MgADP.P(i)-bound state, which is associated with channel activation. The extent of MgADP-dependent activation of K(ATP) channel activity was unaffected by the R826W mutation, but the time course of deactivation was slowed. Channel inhibition by MgATP was reduced, leading to an increase in resting whole-cell currents. In pancreatic beta cells, this would lead to less insulin secretion and thereby diabetes.
K（ATP）通道的成孔亚基Kir6.2（KCNJ11）和调节亚基磺脲类受体SUR1（ABCC8）的激活突变是短暂性新生儿糖尿病（TNDM）的常见病因。我们在SUR1的第一个核苷酸结合结构域（NBD1）中鉴定出一种新的TNDM突变（R826W）。该突变位于与NBD2异二聚化形成催化位点2的区域。功能分析表明，这种突变降低了纯化的麦芽糖结合蛋白MBP-NBD1融合蛋白的MgATP水解。MgADP或BeF对ATP水解的抑制作用没有改变。结果表明，ATP酶循环停留在水解后的MgADP.P（i）结合状态，这与通道激活有关。R826W突变不影响MgADP依赖性K（ATP）通道活性激活的程度，但失活的时间进程减慢。MgATP对通道的抑制作用减弱，导致静息全细胞电流增加。在胰腺β细胞中，这将导致胰岛素分泌减少，从而引发糖尿病。
